Drugs containing phosphoric acid derivatives as the active ingredient

Abstract

The present invention relates to phosphoric acid derivatives represented by general formula (I), wherein each symbol is as defined in the description and nontoxic salts thereof.Because of having a TNFalpha production inhibitory effect, the compounds represented by general formula (I) are useful as preventives and/or remedies for rheumatoid arthritis, ulcerative colitis, Crohn's disease, hepatitis, sepsis, hemorrhagic shock, multiple sclerosis, cerebral infarction, diabetes, interstitial pneumonia, uveitis, pain, glomerulonephritis, HIV-associated diseases, cachexia, myocardial infarction, chronic heart failure, oral aphtha, Hansen's disease, infection, etc.

What is claimed is:  
     
       1. Phosphoric acid derivatives of the formula (I)                    
       wherein R 1  is  
       (1) C1-20 alkyl,  
       (2) C1-20 alkyl which one carbon atom is replaced by an oxygen atom, a sulfur atom, —S(O)— or S(O) 2 — (with the proviso that, a carbon atom which attached with E is not replaced by these groups),  
       (3) C2-20 alkenyl,  
       (4) C2-20 alkynyl,  
       (5) Cyc 1  (wherein Cyc 1  is C5-15 membered mono-, bi- or tricarbocyclic ring or 5-15 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom),  
       (6) C1-20 alkyl, C2-20 alkenyl or C2-20 alkynyl substituted by Cyc 1  (wherein all symbols are the same meaning as hereinbefore defined), Cyc 1  may be substituted by one or more substituents selected from the following (a)-(r):  
       (a) C1-8 alkyl,  
       (b) C1-8 alkoxy,  
       (c) nitro,  
       (d) halogen atom,  
       (e) trfluoromethyl,  
       (f) trifluoromethyloxy,  
       (g) hydroxy,  
       (h) cyano,  
       (i) NR 10 R 11  (wherein R 10  and R 11  each, independently, is a hydrogen atom, C1-8 alkyl, C1-8 hydroxyalkyl, C2-5 acyl or C1-8 alkylsulfonyl),  
       (j) COOR 20  (wherein R 20  is a hydrogen atom or C1-4 alkyl),  
       (k) CONR 30 R 31  (wherein R 30  and R 31  each, independently, is a hydrogen atom or C1-4 alkyl),  
       (l) —S(O) m —R 32  (wherein m is 0, 1 or 2, R 32  is 1-8 alkyl or C1-8 alkyl substituted by C1-8 alkoxy, COOR 20  (wherein R 20  is the same meaning as hereinbefore defined) or CONR 30 R 31  (wherein R 30  and R 31  each, independently, is a hydrogen atom or C1-4 alkyl)),  
       (m) —O—Cyc 2  (wherein Cyc 2  is C3-8 cycloalkyl or phenyl),  
       (n) —S—Cyc 2  (wherein Cyc 2  is the same meaning as hereinbefore defined),  
       (o) C1-8alkyl substituted by one substituent selected from C1-8 alkoxy, COOR 20  (wherein R 20   is the same meaning as hereinbefore defined), CONR 30 R 31  (wherein R 30  and R 31  are the same meaning as hereinbefore defined), phenyl or hydroxy,  
       (p) C1-8alkoxy substituted by one substituent selected from C1-8 alkoxy, COOR 20  (wherein R 20  is the same meaning as hereinbefore defined), CONR 30 R 31  (wherein R 30  and R 31  are the same meaning as hereinbefore defined), phenyl or hydroxy.  
       (q) C3-15 membered mono-, bi- or tricarbocyclic ring,  
       (r) 5-15 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom,  
       E is  
       (a) —NR 7 CO—,  
       (b) —NR 7 SO 2 —,  
       (c) —NR 7 CONR 8 —,  
       (d) —NR 7 COO—,  
       (e) —CONR 7 —,  
       (f) —NR 7 CS—,  
       (g) —NR 7 CSNR 8 —,  
       (h) —NR 7 CS—O—,  
       (i) —CSNR 7 — or  
       (j) —NR 7 — (wherein R 7  and R 8  each, independently, is a hydrogen or C1-4 alkyl), A ring is C3-15 membered mono-, bi- or tricarbocyclic ring or 5-15 membered mono-, bi- or trycyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom,  
       R 2  is the same meaning as hereinbefore defined substituents (a)-(r),  
       R 3  and R 4    
       i) each, independently, is a hydrogen atom, C1-8 alkyl, C1-8 alkoxy, C1-8 hydroxyalkyl or phenyl, or  
       ii) taken together represents C2-6 alkylene, or  
       iii) one of R 3  or R 4 , taken together with R 2 , represent C1-5 alkylene, and the other one is a hydrogen atom, C1-8alkyl or C1-8alkoxy,  
       n is an integer of 0, 1 or more,  
       R 5  and R 6  each, independently, is a hydrogen atom, C1-8 alkyl, phenyl, C1-4 alkyl substituted by phenyl, C1-4 alkyl substituted by cyano or C1-4 alkyl substituted by trihalomethyl,  
       Y and Z each, independently, is an oxygen atom or a sulfur atom.  
       with the proviso that, 
       (1) when n is 2 or more integer, then R 2  is the same or different,  
       (2) when R 1  and R 2  contains a sulfur atom, then Y is an oxygen atom, and R 1  and R 2  do not contains a sulfur atom at the same time or a non-toxic salt thereof.  
     
     
       2. A compound according to  claim 1 , wherein A ring is C3-15 membered mono-, bi- or tricarbocyclic ring. 
     
     
       3. A compound according to  claim 1 , wherein A ring is 3-4 membered monocyclichetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom. 
     
     
       4. A compound according to  claim 1 , wherein A ring is 5-7 membered monocyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom. 
     
     
       5. A compound according to  claim 1 , wherein A ring is 8-15 membered monocyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom. 
     
     
       6. A compound according to  claim 1 , wherein A ring is 8-15 membered bi- or tricyclic hetero ring. 
     
     
       7. A compound according to  claim 1 , wherein both R 5  and R 6  are hydrogen. 
     
     
       8. A compound according to  claim 1 , wherein R 5  and R 6  each, independently, is C1-8 alkyl, phenyl, C1-4 alkyl substituted by phenyl, C1-4 alkyl substituted by cyano or C1-4 alkyl substituted by trihalomethyl. 
     
     
       9. A compound according to  claim 1 , wherein one of R 5  or R 6  is a hydrogen, and the other is C1-8 alkyl, phenyl, C1-4 alkyl substituted by phenyl, C1-4 alkyl substituted by cyano or C1-4 alkyl substituted by trihalomethyl. 
     
     
       10. A compound according to  claim 2 , which is 
       (1) Diphenyl-(2R)-2-t-butoxycarbonylamino-2-phenylethylphosphate,  
       (2) Diphenyl-(2R)-2-N-octanoylamino-2-phenylethylphosphate,  
       (3) Phenyl-(2R)-2-octanoylamino-2-phenylethylphosphate,  
       (4) (2R)-2-Octanoylamino-2-cyclohexylethylphosphate,  
       (5) Bis(2,2,2-trichloroethyl)-(2R)-2-t-butoxycarbonylamino-2-phenylethylphosphate,  
       (6) Bis(2,2,2-trichloroethyl)-(2R)-2-octanoylamino-2-phenylethylphosphate,  
       (7) (2R)-2-Octanoylamino-2-phenylethylphosphate,  
       (8) (2S)-2-Octanoylamino-2-phenylethylphosphate,  
       (9) 1-Methyl-2-nonanoylamino-2-phenylethylphosphate,  
       (10) 1-Methyl-2-octanoylamino-2-phenylethylphosphate,  
       (11) 2-Octanoylamino-2-phenyl-1,1-propanoethylphosphate,  
       (12) (1S,2R)-1-Methyl-2-octanoylamino-2-phenylethylphosphate,  
       (13) (1R,2S)-1-Methyl-2-octanoylamino-2-phenylethylphosphate,  
       (14) (1R,2R)-1-Methyl-2-octanoylamino-2-phenylethylphosphate,  
       (15) (1S,2S)-1-Methyl-2-octanoylamino-2-phenylethylphosphate,  
       (16) Dibenzyl-(1R,2R)-1-octanoylaminoindan-2-ylphosphate,  
       (17) (1R,2R)-1-Octanoylaminoindan-2-ylphosphate,  
       (18) (1R,2R)-1-Octanoylaminoindan-2-ylphosphate,  
       (19) (1R,2S)-1-Octanoylaminoindan-2-ylphosphate,  
       (20) Dibenzyl-(2R)-2-(5-phenylpentanoylamino)-2-phenylethylphosphate,  
       (21) (2R)-2-(5-Phenylpentanoylamino)-2-phenylethylphosphate,  
       (22) (2R)-2-Nonanoylamino-2-phenylethylphosphate,  
       (23) (2R)-2-Decanoylamino-2-phenylethyl phosphate,  
       (24) (2R)-2-Undecanoylamino-2-phenylethylphosphate,  
       (25) 2-Heptylaminocarbonyl-2-phenylethylphosphate,  
       (26) (2R)-2-Propionylamino-2-phenylethylphosphate,  
       (27) (2R)-2-Butyrylamino-2-phenylethylphosphate,  
       (28) (2R)-2-Pentanoylamino-2-phenylethylphosphate,  
       (29) (2R)-2-Hexanoylamino-2-phenylethylphosphate,  
       (30) (2R)-2-Heptanoylamino-2-phenylethylphosphate,  
       (31) (2R)-2-Cyclopropylcarbonylamino-2-phenylethylphosphate,  
       (32) (2R)-2-t-Butylcarbonylamino-2-phenylethylphosphate,  
       (33) (2R)-2-Acetylamino-2-phenylethylphosphate,  
       (34) (2R)-2-Ethoxycarbonylamino-2-phenylethylphosphate,  
       (35) (2R)-2-(N-Methyl-N-octanoylamino)-2-phenylethylphosphate,  
       (36) (2R)-2-Hexyloxycarbonylamino-2-phenylethylphosphate,  
       (37) (2R)-2-(2,2-Dimethyloctanoylamino)-2-phenylethylphosphate,  
       (38) (2R)-2-(2,2-Propanooctanoylamino)-2-phenylethylphosphate,  
       (39) (2R)-2-(2-Methyloctanoylamino)-2-phenylethylphosphate,  
       (40) (2R)-2-Benzoylamino-2-phenylethylphosphate,  
       (41) (2R)-2-t-Butoxycarbonylamino-2-phenylethylphosphate,  
       (42) (2R)-2-Octylsulfonylamino-2-phenylethylphosphate,  
       (43) (2R)-2-(N′-Hexylureido)-2-phenylethylphosphate,  
       (44) (2R)-2-Phenyl-2-(4-propyloxybutanoyl)aminoethylphosphate,  
       (45) (2R)-2-(6-Methoxyhexanoyl)amino-2-phenylethylphosphate,  
       (46) (2R)-2-Phenyl-2-(2-propylvaleryl)aminoethylphosphate,  
       (47) (2R)-2-(2-Pentyloxyacetyl)amino-2-phenylethylphosphate,  
       (48) (2R)-2-(5-Ethoxyvaleryl)amino-2-phenylethylphosphate,  
       (49) (1S,2R)-2-Heptanoylamino-1-methyl-2-phenylethylphosphate,  
       (50) (1S,2R)-1-Methyl-2-nonanoylamino-2-phenylethylphosphate,  
       (51) 2-(4-Methoxyphenyl)-2-octanoylaminoethylphosphate,  
       (52) 2-(3-Methoxyphenyl)-2-octanoylaminoethylphosphate,  
       (53) 2-(2-Methoxyphenyl)-2-octanoylaminoethylphosphate,  
       (54) 2-(2-Methylphenyl)-2-octanoylaminoethylphosphate,  
       (55) 2-(3-Methylphenyl)-2-octanoylaminoethylphosphate,  
       (56) 2-(4-Methylphenyl)-2-octanoylaminoethylphosphate,  
       (57) 2-(Naphthalen-1-yl)-2-octanoylaminoethylphosphate,  
       (58) 2-(Naphthalen-2-yl)-2-octanoylaminoethylphosphate,  
       (59) 2-Octanoylamino-2-(4-trifluoromethylphenyl)ethylphosphate,  
       (60) 2-Octanoylamino-2-(2-trifluoromethylphenyl)ethylphosphate,  
       (61) 2-(3,5-Dimethoxyphenyl)-2-octanoylaminoethylphosphate,  
       (62) 2-(3-Fluorophenyl)-2-octanoylaminoethylphosphate,  
       (63) 2-(3-Ethoxyphenyl)-2-octanoylaminoethylphosphate,  
       (64) 2-Octanoylamino-2-(3-propyloxyphenyl)ethylphosphate,  
       (65) 2-(3-Isopropyloxyphenyl)-2-octanoylaminoethylphosphate,  
       (66) 2-Octanoylamino-2-(3-trifluoromethylphenyl)ethylphosphate,  
       (67) (2R)-2-(3-Methoxyphenyl)-2-octanoylaminoethylphosphate,  
       (68) 2-Heptanoylamino-2-(3-methoxyphenyl)ethyphosphate,  
       (69) 2-Hexanoylamino-2-(3-methoxyphenyl)ethylphosphate,  
       (70) 2-(3-Methoxyphenyl)-2-valerylaminoethylphosphate,  
       (71) 2-(3-(2-Methoxyethoxy)phenyl)-2-octanoylaminoethylphosphate,  
       (72) 2-(3-Butoxyphenyl)-2-octanoylaminoethylphosphate,  
       (73) 2-Octanoylamino-2-(3-pentyloxyphenyl)ethylphosphate,  
       (74) 2-(3-Hexyloxyphenyl)-2-octanoylaminoethylphosphate,  
       (75) 2-(3-Methoxymethylphenyl)-2-octanoylaminoethylphosphate,  
       (76) 2-(3-Cyclopentyloxyphenyl)-2-octanoylamnoethylphosphate,  
       (77) 2-(3-(2-Methylpropyloxy)phenyl)-2-octanoylaminoethylphosphate,  
       (78) 2-Acetylamino-2-(3-methoxyphenyl)ethylphosphate,  
       (79) 2-octanoylamino-2-(3-trifluoromethyloxyphenyl)ethylphosphate,  
       (80) 2-(3-Dimethylaminocarbonylmethyloxyphenyl)-2-octanoylaminoethylphosphate,  
       (81) (2S)-2-(3-methoxyphenyl)-2-octanoylaminoethylphosphate,  
       (82) 2-(3-Cyclobutyloxyphenyl)-2-octanoylaminoethylphosphate,  
       (83) 2-(3-(1-Ethylpropyloxy)phenyl)-2-octanoylaminoethylphosphate,  
       (84) 2-(3-Methoxymethoxyphenyl)-2-octanoylaminoethylphosphate,  
       (85) (1S,2R)-2-(3-Methoxyphenyl)-1-methyl-2-octanoylaminoethylphosphate,  
       (86) (1S,2R)-2-(3-Isopropyloxyphenyl)-1-methyl-2-octanoylaminoethylphosphate,  
       (87) (1R,2R)-2-(3-Methoxyphenyl)-1-methyl-2-octanoylaminoethylphosphate,  
       (88) (1R,2S)-2-(3-Methoxyphenyl)-1-methyl-2-octanoylaminoethylphosphate,  
       (89) (1S,2S)-2-(3-Methoxyphenyl)-1-methyl-2-octanoylaminoethylphosphate,  
       (90) Di-t-butyl-(2R)-2-pentylthioacetylamino-2-phenylethylphosphate,  
       (91) (2R)-2-Pentylthioacetylamino-2-phenylethylphosphate,  
       (92) (2R)-2-Pentylthioacetylamino-2-phenylethylphosphate,  
       (93) 2-(4-Chlorophenyl)-2-octanoylaminoethylphosphate,  
       (94) (1S,2R -1-Methyl-2-(2-pentylthioacetyl)amino-2-phenylethylphosphate,  
       (95) 2-(3-Chorophenyl)-2-octanoylaminoethylphosphate,  
       (96) 2-(2-Chlorophenyl)-2-octanoylaminoethylphosphate,  
       (97) 2-(3-Methylthiophenyl)-2-octanoylaminoethylphosphate,  
       (98) 2-(3-Methylsulfonyphenyl)-2-octanoylaminoethylphosphate,  
       (99) 2-(3-Isopropylthiophenyl)-2-octanoylaminoethylphosphate,  
       (100) (2R)-Bis(2-cyanoethyl)-2-octanoylamino-2-phenylethylthiophosphate,  
       (101) (2R)-2-Octanoylamino-2-phenylethylthiophosphoric acid,  
       (102) (1S,2R)-[Bis(2-cyanoethyl)]-1,2-diphenyl-2-octanoylaminoethylphosphate,  
       (103) (1S,2R)-2-Octanoylamino-1,2-diphenylethylphosphate,  
       (104) 2-Octanoylamino-2-(3-benzyloxyphenyl)ethylphosphate,  
       (105) Diethyl-(2R)-S-(2-t-butoxycarbonylamino-2-phenyl)ethanephosphorothioate,  
       (106) (2R)-S-(2-Octanoylamino-2-phenylethyl)-O,O′-diethylphosphorothioate,  
       (107) (2R)-S-(2-Octanoylamino-2-phenylethyl)phosphorothioate,  
       (108) 2-(3-Hydroxyphenyl)-2-octanoylaminoethylphosphate,  
       (109) 2-(3-Hydroxymethylphenyl)-2-octanoylaminoethylphosphate,  
       (110) (1S,2R)-2-(3-Hydroxymethylphenyl)-1-methyl-2-octanoylaminoethylphosphate,  
       (111) 2-(3-Ethoxycarbonylmethoxyphenyl)-2-octanoylaminoethylphosphate,  
       (112) (1S,2R)-2-(3-Methoxycarbonylphenyl)-1-methyl-2-octanoylaminoethylphosphate,  
       (113) 2-(3-Methoxycarbonylmethylphenyl)-2-octanoylaminoethylphosphate,  
       (114) 2-(3-Methoxyphenyl)-1,1-dimethyl-2-octanoylaminoethylphosphate,  
       (115) 2-(3-Methylsulfonylaminophenyl)-2-octanoylaminoethylphosphate,  
       (116) (1S,2R)-2-(3-Methoxycarbonylmethylphenyl)-1-methyl-2-octanoylaminoethylphosphate,  
       (117) 2-(3-Methoxycarbonylphenyl)-2-octanoylaminoethylphosphate,  
       (118) (1S,2R)-2-Hexyloxycarbonylamino-1-methyl-2-(3-methoxyphenyl)ethylphosphate,  
       (119) (1S,2R)-2-Hexyloxycarbonylamino-1-methyl-2-phenylethylphosphate,  
       (120) (1S,2R)-2-Hexyloxycarbonylamino-1-methyl-2-(3-isopropyloxyphenyl)ethylphosphate,  
       (121) (1S,2R)-2-Hexyloxycarbonylamino-2-(3-methoxycarbonylphenyl)1-methylethylphosphate,  
       (122) (1S,2R)-1-Methyl-2-(3-methylthiophenyl)-2-octanoylaminoethylphosphate,  
       (123) (1S,2R)-2-Hexyloxycarbonylamino-1-methyl-2-(3-methylthiophenyl)ethylphosphate,  
       (124) (1R,2R)-1-Hydroxymethyl-2-octanoylamino-2-phenylethylphosphate,  
       (125) 2-(3-Carboxyphenyl)-2-octanoylaminoethylphosphate,  
       (126) 2-(3-Carboxymethylphenyl)-2-octanoylaminoethylphosphate,  
       (127) (2R)-2-(2-Pentylsulfonylacetyl)amino-2-phenylethylphosphate,  
       (128) (2R)-2-(4-Hydroxyphenyl)-2-octanoylaminoethylphosphate or  
       (129) Diphenyl-(1S,2R)-2-(3-methoxyphenyl)-1-methyl-2-octanoylaminoethylphosphate,  
       or a non-toxic salt thereof. 
     
     
       11. A compound according to  claim 4 , which is 
       (1) 2-(1,3-Dioxaindan-5-yl)-2-octanoylaminoethylphosphate or  
       (2) 2-(1,3-Dioxaindan-4-yl)-2-octanoylaminoethylphosphate,  
       or a non-toxic salt thereof. 
     
     
       12. A compound according to  claim 5 , which is 
       (1) 2-Octanoylamino-2-(thiophen-2-yl)ethylphosphate,  
       (2) 2-Octanoylamino-2-(pyridin-2-yl)ethylphosphate or  
       (3) 2-Octanoylamino-2-(pyridin-3-yl)ethylphosphate,  
       or a non-toxic salt thereof. 
     
     
       13. A TNFa production inhibitor, which comprises a phosphoric acid derivative having the formula (I) depicted in  claim 1  or non-toxic salt thereof. 
     
     
       14. A compound for the prevention and/or treatment of rheumatoid arthritis, ulcerative colitis, Crohn's disease, hepatitis, sepsis, hemorrhagic shock, multiple sclerosis, cerebral infarction, diabetes, interstitial pneumonia, uveitis, pain, glomerulonephritis, HIV-associated diseases, cachexia, myocardial infarction, chronic heart failure, oral aphtha, Hansen's disease, infection, which comprises a phosphoric acid derivative having the formula (I) depicted in  claim 1  or non-toxic salt thereof. 
     
     
       15. A pharmaceutical composition which comprises, as an active ingredient, a phosphoric acid derivative having the formula (I) depicted in  claim 1  or a non-toxic salt thereof.